TWI822897B - Use of anti-pd-1 antibody in combination with famitinib for preparation of medicament for treating tumor diseases - Google Patents
Use of anti-pd-1 antibody in combination with famitinib for preparation of medicament for treating tumor diseases Download PDFInfo
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- TWI822897B TWI822897B TW108140100A TW108140100A TWI822897B TW I822897 B TWI822897 B TW I822897B TW 108140100 A TW108140100 A TW 108140100A TW 108140100 A TW108140100 A TW 108140100A TW I822897 B TWI822897 B TW I822897B
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Abstract
Description
本公開中涉及一種抗PD-1抗體和法米替尼或其可藥用鹽聯合在製備治療腫瘤的藥物中的用途。 The present disclosure relates to the use of an anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.
癌症具有許多遺傳和表觀遺傳改變,產生可被免疫系統識別的新抗原。適應性免疫系統,包括T和B淋巴細胞,具有強大的抗癌潛力,具有廣泛的能力和精細的特異性,以響應各種腫瘤抗原。此外,免疫系統表現出相當大的可塑性和記憶成分。成功利用適應性免疫系統的所有這些屬性將使免疫治療在所有癌症治療模式中是獨特的。 Cancers have many genetic and epigenetic alterations that produce neoantigens that are recognized by the immune system. The adaptive immune system, including T and B lymphocytes, has strong anticancer potential, with broad capabilities and refined specificity to respond to various tumor antigens. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.
癌症免疫治療已經集中在藉由激活的效應細胞的過繼轉移,針對相關抗原的免疫或提供非特異性免疫刺激劑如細胞因子來增強抗腫瘤免疫反應的方法上。近年來,開發特異性免疫檢查點途徑抑制劑已經開始成為一種新的治療癌症的免疫治療方法,例如用於治療晚期黑色素瘤的CTLA抗體Ipilimumab (YERVOY®)(Hodi等人,2010),特異性結合程序性死亡受體(PD-1)nivolumab或pembrolizumab等。 Cancer immunotherapy has focused on approaches to enhance anti-tumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or delivery of nonspecific immune stimulators such as cytokines. In recent years, the development of specific immune checkpoint pathway inhibitors has begun to become a new immunotherapy approach to treat cancer, such as the CTLA antibody Ipilimumab ( YERVOY® ) for the treatment of advanced melanoma (Hodi et al., 2010), which specifically Combined with programmed death receptor (PD-1) nivolumab or pembrolizumab, etc.
PD-1抗體特異性識別並結合淋巴細胞表面PD-1,阻斷PD-1/PD-L1信號通路,進而激活T細胞對腫瘤的免疫殺傷作用,調動機體免疫系統而清除體內腫瘤細胞。WO2015085847公開了一種新的抗PD-1抗體,目前PD-1抗體正處於臨床試驗階段,已經顯示出一定的抗腫瘤作用。 PD-1 antibodies specifically recognize and bind to PD-1 on the surface of lymphocytes, blocking the PD-1/PD-L1 signaling pathway, thereby activating the immune killing effect of T cells on tumors, mobilizing the body's immune system to eliminate tumor cells in the body. WO2015085847 discloses a new anti-PD-1 antibody. The PD-1 antibody is currently in the clinical trial stage and has shown certain anti-tumor effects.
在一項法米替尼二線或二線以上標準化療失敗的晚期/轉移性結直腸腺癌的多中心隨機雙盲安慰劑對照II期試驗中,法米替尼組(25mg,1天/次,42天為一個週期)較安慰劑組可改善晚期/轉移性結直腸癌患者無進展生存期(PFS)1.3個月(HR為0.596,P為0.0053)。客觀緩解率(ORR)為2.2%,疾病控制率(DCR)為59.8%),中位生存期(mOS)為7.5個月,安慰劑組為7.6個月,且不良事件可控。結構如下: In a multicenter, randomized, double-blind, placebo-controlled phase II trial of famitinib (25 mg, 1 day/ times, 42 days as a cycle) can improve the progression-free survival (PFS) of patients with advanced/metastatic colorectal cancer by 1.3 months compared with the placebo group (HR is 0.596, P is 0.0053). The objective response rate (ORR) was 2.2%, the disease control rate (DCR) was 59.8%), the median survival time (mOS) was 7.5 months, compared with 7.6 months in the placebo group, and adverse events were controllable. The structure is as follows:
目前已有多個PD-1抗體與VEGFR抑制劑(如舒尼替尼,索拉菲尼等)聯合療法正處於臨床II/III期,適應症分別為惡性肝癌(索拉菲尼與PD-1抗體聯用)和轉移性腎細胞癌(舒尼替尼與PD-1抗體聯用),初步結果顯示兩種藥物聯用效果均優於單藥,但尚未見法米替尼與PD-1抗體聯用的報告。 Currently, there are multiple combination therapies of PD-1 antibodies and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) in clinical phase II/III, with indications for malignant liver cancer (sorafenib and PD- 1 antibody combined) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibody), preliminary results show that the combined effect of both drugs is better than that of single drugs, but famitinib has not been combined with PD-1 antibody. 1Report on antibody combination.
本公開中提供了一種抗PD-1抗體或其抗原結合片段和法米替尼或其可藥用鹽聯合在製備治療腫瘤的藥物中的用途。 The present disclosure provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors.
PD-1抗體是已知的,較佳該PD-1抗體的輕鏈可變區包含分別如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3。 PD-1 antibodies are known. Preferably, the light chain variable region of the PD-1 antibody includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively. .
該PD-1抗體的重鏈可變區包含分別如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。 The heavy chain variable region of the PD-1 antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively.
其中,前面所述的各CDR序列如下表所示: Among them, the CDR sequences mentioned above are shown in the following table:
較佳的,該PD-1抗體為人源化抗體。 Preferably, the PD-1 antibody is a humanized antibody.
在一些實施方案中,該人源化抗體包含SEQ ID NO:10所示的輕鏈可變區或其變體,該變體較佳在SEQ ID NO:10所示的輕鏈可變區有0-10的胺基酸變化,更佳A43S的胺基酸變化;該人源化抗體包含SEQ ID NO:9所示的重鏈可變區或其變體,該變體較佳在SEQ ID NO:9所示的重鏈可變區有0-10的胺基酸變化,更佳G44R的胺基酸變化。 In some embodiments, the humanized antibody comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has a light chain variable region shown in SEQ ID NO: 10. The amino acid change of 0-10, preferably the amino acid change of A43S; the humanized antibody includes the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, and the variant is preferably in SEQ ID NO: The heavy chain variable region shown in NO: 9 has an amino acid change of 0-10, preferably the amino acid change of G44R.
前述的人源化抗體重、輕鏈可變區的序列如下所示: The sequences of the heavy and light chain variable regions of the aforementioned humanized antibodies are as follows:
SEQID NO:9 SEQ ID NO: 9
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK SEQID NO:10 DIQMTQSPSSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK SEQID NO: 10
在另一些實施方案中,該人源化抗體包含SEQ ID NO:8所示的輕鏈或其變體,該變體較佳在輕鏈可變區有0-10的胺基酸變化,更佳A43S的胺基酸變化;該人源化抗體包含SEQ ID NO:7所示的重鏈或其變體,該變體較佳在重鏈可變區有0-10的胺基酸變化,更佳G44R的胺基酸變化。 In other embodiments, the humanized antibody comprises the light chain shown in SEQ ID NO: 8 or a variant thereof. The variant preferably has 0-10 amino acid changes in the light chain variable region, and more Preferably, the amino acid change of A43S; the humanized antibody includes the heavy chain shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has an amino acid change of 0-10 in the heavy chain variable region, Better amino acid changes of G44R.
在另一實施方案中,該人源化抗體含有如SEQ ID NO:8所示的輕鏈,和如SEQ ID NO:7所示的重鏈。 In another embodiment, the humanized antibody contains a light chain as set forth in SEQ ID NO:8, and a heavy chain as set forth in SEQ ID NO:7.
該人源化抗體重、輕鏈的序列如下所示: The sequences of the heavy and light chains of the humanized antibody are as follows:
SEQID NO:7 SEQ ID NO: 7
SEQID NO:8 SEQ ID NO: 8
本公開中所述聯合抗PD-1抗體或其抗原結合片段和法米替尼或其可藥用鹽具有協同藥效作用。 The combination of anti-PD-1 antibodies or antigen-binding fragments thereof and famitinib or pharmaceutically acceptable salts thereof described in the present disclosure has a synergistic pharmacodynamic effect.
本公開中所述的用途,根據患者體重給藥,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為0.1~10.0mg/kg,可以為0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、 7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或任意兩數值間任意值。 For the uses described in this disclosure, the dosage of the anti-PD-1 antibody or its antigen-binding fragment in human subjects is 0.1 to 10.0 mg/kg, and can be 0.1 mg/kg, 0.2 mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4 mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4 mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4 mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4 mg/kg、7.6mg/kg、 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg or any value between any two values.
在可選實施方案中,其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為10~300mg,可以為10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg或任意兩數值間任意值,較佳50~300mg,最佳200mg。 In an optional embodiment, the dosage of the PD-1 antibody or antigen-binding fragment thereof in human subjects is 10 to 300 mg, and can be 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg , 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg , 300mg or any value between any two values, preferably 50~300mg, and the best 200mg.
本公開中所述抗PD-1抗體或其抗原結合片段的給藥頻為一天一次、兩天一次、三天一次、四天一次、五天一次、六天一次、一週一次、二週一次、三週一次、四週一次或一月一次,較佳三週一次。 The administration frequency of the anti-PD-1 antibody or antigen-binding fragment thereof described in this disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, Once every three weeks, once every four weeks or once a month, preferably once every three weeks.
在可選實施方案中,本公開中所述抗PD-1抗體或其抗原結合片段給藥劑量為50~300mg/2-3週一次,更佳為200mg/2-3週一次。 In an optional embodiment, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is 50 to 300 mg/once every 2-3 weeks, and more preferably 200 mg/once every 2-3 weeks.
本公開中所述的用途,根據患者體重給藥,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為0.1~10.0mg/kg,可以為0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、 6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或任意兩數值間任意值。 For the uses described in this disclosure, the dosage of famitinib or its pharmaceutically acceptable salt in human subjects is 0.1 to 10.0 mg/kg, which can be 0.1 mg/kg, 0.2 mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4 mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4 mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4 mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg or any value between any two values.
在可選實施方案中,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為0.1~100mg,可以為0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg或任意兩數值間任意值,較佳1~20mg。 In an optional embodiment, the dosage of famitinib or a pharmaceutically acceptable salt thereof in human subjects is 0.1 to 100 mg, and can be 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg or any value between any two values, whichever is greater Preferably 1~20mg.
本公開中所述的用途,其中,該法米替尼或其可藥用的給藥頻率為一天一次,兩天一次,三天一次,四天一次,五天一次,六天一次,一週一次,每週給藥三天、一天一次,每週給藥四天、一天一次,每週給藥五天、一天一次。 The use described in the present disclosure, wherein the famitinib or its pharmaceutically acceptable administration frequency is once a day, once every two days, once three days, once four days, once five days, once six days, once a week , administered once a day three days a week, once a day four days a week, and once a day five days a week.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為10~300mg,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為0.1~100mg。 In an optional embodiment, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in human subjects is 10 to 300 mg, and the dosage of famitinib or pharmaceutically acceptable salts thereof in human subjects is The dosage is 0.1~100mg.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為10~300mg,2-3週一次,該法米替尼或其可藥用鹽給藥在人類受試者中的施用劑量為0.1~100mg,一天一次。 In an optional embodiment, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in human subjects is 10 to 300 mg, once every 2 to 3 weeks, and the famitinib or pharmaceutically acceptable salt thereof is administered The drug is administered to human subjects at a dose of 0.1 to 100 mg once a day.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為50~300mg,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg。 In an optional embodiment, the dosage of the anti-PD-1 antibody or its antigen-binding fragment in human subjects is 50 to 300 mg, and the dosage of famitinib or its pharmaceutically acceptable salt in human subjects is The dosage is 1~20mg.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為50~300mg,2-3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg,一天一次。 In an optional embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to human subjects at a dose of 50 to 300 mg, once every 2 to 3 weeks, and the famitinib or pharmaceutically acceptable salt thereof is administered in human subjects. The dosage in human subjects is 1 to 20 mg once daily.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為200mg,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg。 In an alternative embodiment, the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in human subjects is 200 mg, and the dosage of famitinib or a pharmaceutically acceptable salt thereof in human subjects is 200 mg. It is 1~20mg.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為200mg,2-3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg,一天一次。 In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in human subjects at a dose of 200 mg, once every 2-3 weeks, and the famitinib or pharmaceutically acceptable salt thereof is administered in human subjects. The dosage for subjects is 1 to 20 mg, once a day.
在可選實施方案中,該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為200mg,3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg,一天一次。 In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in human subjects at a dose of 200 mg, once every 3 weeks, and the famitinib or pharmaceutically acceptable salt thereof is administered in human subjects The dosage is 1~20mg, once a day.
另一方面,在可選實施方案中,本公開用途中,相比於單獨施用同等劑量的法米替尼或其可藥用鹽,該法米替尼或其可藥用鹽的AUC提高了至少15%(包括15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%或更高),較佳至少20%,最佳至少25%。 In another aspect, in an alternative embodiment, the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased compared to administration of an equivalent dose of famitinib or a pharmaceutically acceptable salt thereof alone. At least 15% (including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or higher), preferably at least 20%, and best at least 25%.
在可選實施方案中,本公開用途中,相比於單獨施用同等劑量的法米替尼或其可藥用鹽,該法米替尼或其可藥用鹽的Cmax提高了至少15%(包括15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%或更高),較佳至少20%。 In an alternative embodiment, the Cmax of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15% compared to an equivalent dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. (Including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or higher), preferably at least 20%.
在本公開中較佳的實施方案中,該PD-1抗體以注射的方式給藥,例如皮下或靜脈注射,注射前需將PD-1抗體配製成可注射的形式。特別佳的PD- 1抗體的可注射形式是注射液或凍乾粉針,其包含PD-1抗體、緩衝劑、穩定劑,任選地還含有表面活性劑。緩衝劑可選自醋酸鹽、檸檬酸鹽、琥珀酸鹽、以及磷酸鹽中的一種或幾種。穩定劑可選自糖或胺基酸,較佳二糖,例如蔗糖、乳糖、海藻糖、麥芽糖。表面活性劑選自聚氧乙烯氫化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯,較佳該聚氧乙烯山梨醇酐脂肪酸酯為聚山梨酯20、40、60或80,最佳聚山梨酯20。最為佳的PD-1抗體的可注射形式包含PD-1抗體、醋酸鹽緩衝劑、海藻糖和聚山梨酯20。 In a preferred embodiment of the present disclosure, the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody needs to be formulated into an injectable form before injection. Particularly good PD- The injectable form of the 1 antibody is an injection or a lyophilized powder injection, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffering agent may be selected from one or more of acetate, citrate, succinate, and phosphate. Stabilizers can be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, and maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. Preferably, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80. , Best Polysorbate 20. The most preferred injectable form of PD-1 antibody contains PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
本公開中提供上述抗PD-1抗體聯合法米替尼或其可藥用鹽作為治療製備治療腫瘤的藥物。 The present disclosure provides the above-mentioned anti-PD-1 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a drug for the preparation and treatment of tumors.
本公開中提供上述抗PD-1抗體聯合法米替尼或其可藥用鹽作為減少藥物不良反應的藥物,較佳的,該藥物不良反應選自由抗PD-1抗體引起或由法米替尼或其可藥用鹽引起。 The present disclosure provides the above-mentioned anti-PD-1 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. Preferably, the adverse drug reaction is selected from being caused by anti-PD-1 antibodies or caused by famitinib. Ni or its pharmaceutically acceptable salts.
在可選實施方案中,本公開用途中所述不良反應較佳抗PD-1抗體的不良反應,最佳反應性毛細血管增生症。 In alternative embodiments, the adverse reaction described in the disclosed uses is preferably an adverse reaction of an anti-PD-1 antibody, preferably reactive capillary hyperplasia.
在一些實施方案中,相比於單獨施用同等劑量的抗PD-1抗體(如重、輕鏈的序列如本公開中SEQID NO:7和SEQID NO:8),該反應性毛細血管增生症發生率不高於15%(包括15%、14.5%、14%、13.5%、13%、12.5%、12%、11.5%、11%、10.5%、10%、9.5%、9%、8.5%、8%、7.5%、7%、6.5%、6%、5.5%、5%、4%、4.5%、3.5%、3%、2.5%、2%、1.5%、1%或更低),較佳不高於2.5%。 In some embodiments, the reactive capillary hyperplasia occurs compared to administration of an equivalent dose of an anti-PD-1 antibody (e.g., heavy and light chain sequences such as SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure) alone. The rate is not higher than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or lower), less The best is no more than 2.5%.
本公開中提供上述抗PD-1抗體聯合法米替尼或其可藥用鹽作為降低抗PD-1抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的藥物。 The present disclosure provides the above anti-PD-1 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a medicine for reducing the dosage of the anti-PD-1 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof alone.
在本公開中,提供了一種治療腫瘤的辦法,包括向患者施用上述抗PD-1抗體和法米替尼或其可藥用鹽。 In the present disclosure, a method of treating tumors is provided, comprising administering the above-mentioned anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof to a patient.
在本公開中,提供了一種降低抗PD-1抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的方法,包括向患者施用上述抗PD-1抗體聯合法米替尼或其可藥用鹽。 In the present disclosure, a method for reducing the dosage of an anti-PD-1 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof is provided, comprising administering the above-mentioned anti-PD-1 antibody in combination with famitinib to a patient. Ni or its pharmaceutically acceptable salt.
在另一些實施方案中,與PD-1聯合使用時,該法米替尼或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%(包括10%、15%、20%、30%、35%、40%、45%、50%、55%、60%、70%、75%、80%、90%、95%),較佳10%~75%,更佳75%、50%、25%、12.5%。 In other embodiments, when used in combination with PD-1, the dosage of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% (including 10%, 15%, 20%) of the dosage administered alone. %, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10%~75%, preferably 75 %, 50%, 25%, 12.5%.
在另一些實施方案中,與法米替尼或其可藥用鹽聯用時,抗PD-1抗體劑量是抗PD-1抗體單獨施用劑量的10%~100%(包括10%、15%、20%、30%、35%、40%、45%、50%、55%、60%、70%、75%、80%、90%、95%),較佳10%~50%。 In other embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the anti-PD-1 antibody dose is 10% to 100% (including 10%, 15%) of the anti-PD-1 antibody dose administered alone. , 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10%~50%.
本公開還提供了一種降低抗PD-1抗體或其抗原結合片段、法米替尼或其可藥用鹽導致的不良反應的方法,包括向患者聯合施用法米替尼或其可藥用鹽和前述的PD-1抗體,該不良反應較佳抗PD-1抗體的不良反應,最佳反應性毛細血管增生症。 The present disclosure also provides a method for reducing adverse reactions caused by an anti-PD-1 antibody or an antigen-binding fragment thereof, famitinib or a pharmaceutically acceptable salt thereof, comprising co-administering famitinib or a pharmaceutically acceptable salt thereof to a patient As with the aforementioned PD-1 antibodies, the adverse reactions are better than those of anti-PD-1 antibodies, and the best adverse reactions are reactive capillary hyperplasia.
在可選實施方案中,本公開所述不良反應較佳抗PD-1抗體的不良反應,最佳反應性毛細血管增生症。 In alternative embodiments, the adverse reactions described in the present disclosure are preferably adverse reactions of anti-PD-1 antibodies, preferably reactive capillary hyperplasia.
在一些實施方案中,相比於單獨施用同等劑量的抗PD-1抗體(如重、輕鏈的序列如本公開中SEQID NO:7和SEQID NO:8),該反應性毛細血管增生症發生率不高於15%(包括15%、14.5%、14%、13.5%、13%、12.5%、12%、11.5%、11%、10.5%、10%、9.5%、9%、8.5%、8%、7.5%、7%、6.5%、6%、5.5%、5%、4%、4.5%、3.5%、3%、2.5%、2%、1.5%、1%或更低),較佳不高於2.5%。 In some embodiments, the reactive capillary hyperplasia occurs compared to administration of an equivalent dose of an anti-PD-1 antibody (e.g., heavy and light chain sequences such as SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure) alone. The rate is not higher than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or lower), less The best is no more than 2.5%.
本公開中還提供了一種藥物套組,或者一種藥物包裝盒,或者藥物組合,其中含有法米替尼或其可藥用鹽,和PD-1抗體。 The present disclosure also provides a pharmaceutical kit, or a pharmaceutical packaging box, or a pharmaceutical combination, which contains famitinib or a pharmaceutically acceptable salt thereof, and a PD-1 antibody.
本公開中還提供了一種抗PD-L1抗體或抗CTAL-4抗體,和法米替尼或其可藥用鹽聯合在製備治療腫瘤的藥物中的用途。 The present disclosure also provides the use of an anti-PD-L1 antibody or an anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.
在可選實施方案中,根據患者體重給藥,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合在人類受試者中的施用劑量為0.1~10.0mg/kg,可以為0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg。 In an optional embodiment, the dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding thereof in human subjects is 0.1 to 10.0 mg/kg according to the patient's body weight. , can be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg /kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg /kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg /kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg /kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg /kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg.
在另一可選實施方案中,其中該PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為50~700mg,可以為50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg,較佳50~600mg,最佳200mg。 In another optional embodiment, the dosage of the PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof in human subjects is 50 to 700 mg, which may be 50 mg or 55 mg. , 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg , 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg , 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg , 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg , 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg , 685mg, 690mg, 695mg, 700mg, preferably 50~600mg, and the best 200mg.
本公開中所述抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段的給藥頻為一天一次、兩天一次、三天一次、四天一次、五天一次、六天一次、一週一次、二週一次、三週一次、四周一次或一月一次。 The administration frequency of the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment described in this disclosure is once a day, once every two days, once every three days, once every four days, once every five days, Once every six days, once a week, once every two weeks, once every three weeks, once every four weeks or once a month.
在可選實施方案中,本公開中所述抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為50~600mg/2-3週一次,更佳為200mg/2-3週一次。 In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof described in the present disclosure is administered in human subjects at a dose of 50 to 600 mg/2-3 Once a week, preferably 200mg/2-3 weeks.
在可選實施方案中,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為50~700mg,2-3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為為0.1~100mg,一天一次。 In an optional embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to human subjects at a dose of 50 to 700 mg, once every 2 to 3 weeks. Famitinib or its pharmaceutically acceptable salts are administered to human subjects at a dose of 0.1 to 100 mg once a day.
在可選實施方案中,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為50~600mg,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg。 In an optional embodiment, the dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof in human subjects is 50 to 600 mg, and the famitinib or its Pharmaceutically acceptable salts are administered to human subjects at doses of 1 to 20 mg.
在可選實施方案中,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為50~600mg,2-3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg,一天一次。 In an optional embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to human subjects at a dose of 50 to 600 mg, once every 2 to 3 weeks. Famitinib or its pharmaceutically acceptable salts are administered to human subjects at a dose of 1 to 20 mg once daily.
在可選實施方案中,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為200mg,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg。 In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered in a human subject at a dose of 200 mg, the famitinib or its druggable The dosage of salt administered to human subjects is 1 to 20 mg.
在可選實施方案中,該抗PD-L1抗體或其抗原結合片段或抗CTAL-4抗體或其抗原結合片段在人類受試者中的施用劑量為200mg,2-3週一次,該法米替尼或其可藥用鹽在人類受試者中的施用劑量為1~20mg,一天一次。 In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered in human subjects at a dose of 200 mg, once every 2-3 weeks, and the Famibo Tinib or its pharmaceutically acceptable salts are administered to human subjects at a dose of 1 to 20 mg once a day.
在本公開中較佳的實施方案中,該PD-L1抗體或抗CTAL-4抗體以注射的方式給藥,例如皮下或靜脈注射,注射前需將PD-L1抗體或抗CTAL-4抗體配製成可注射的形式。 In a preferred embodiment of the present disclosure, the PD-L1 antibody or anti-CTAL-4 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-L1 antibody or anti-CTAL-4 antibody needs to be formulated before injection. Made into an injectable form.
本公開中提供上述抗PD-L1抗體或抗CTAL-4抗體聯合法米替尼或其可藥用鹽作為減少藥物不良反應的藥物,較佳的,該藥物不良反應選自由抗PD-L1抗體或抗CTAL-4抗體引起或由法米替尼或其可藥用鹽引起。 The present disclosure provides the above-mentioned anti-PD-L1 antibody or anti-CTAL-4 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. Preferably, the adverse drug reaction is selected from the group consisting of anti-PD-L1 antibodies. or caused by anti-CTAL-4 antibodies or by famitinib or its pharmaceutically acceptable salts.
本公開中提供上述抗PD-L1抗體聯合法米替尼或其可藥用鹽作為降低抗PD-L1抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的藥物。 The present disclosure provides the above anti-PD-L1 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a medicine for reducing the dosage of the anti-PD-L1 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof alone.
本公開中提供上述抗CTAL-4抗體聯合法米替尼或其可藥用鹽作為降低抗CTAL-4抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的藥物。 The present disclosure provides the above anti-CTAL-4 antibody combined with famitinib or a pharmaceutically acceptable salt thereof as a medicine for reducing the dosage of the anti-CTAL-4 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof alone.
在本公開中,提供了一種治療腫瘤的辦法,包括向患者施用上述抗PD-L1抗體或抗CTAL-4抗體和法米替尼或其可藥用鹽。 In the present disclosure, a method of treating tumors is provided, comprising administering the above-mentioned anti-PD-L1 antibody or anti-CTAL-4 antibody and famitinib or a pharmaceutically acceptable salt thereof to a patient.
在本公開中,提供了一種降低抗PD-L1抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的方法,包括向患者施用上述抗PD-L1抗體聯合法米替尼或其可藥用鹽。 In the present disclosure, a method for reducing the dosage of an anti-PD-L1 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof is provided, comprising administering the above-mentioned anti-PD-L1 antibody in combination with famitinib to a patient. Ni or its pharmaceutically acceptable salt.
在本公開中,提供了一種降低抗CTAL-4抗體單獨施用劑量和/或法米替尼或其可藥用鹽單獨施用劑量的方法,包括向患者施用上述抗CTAL-4抗體聯合法米替尼或其可藥用鹽。 In the present disclosure, a method for reducing the dosage of an anti-CTAL-4 antibody alone and/or the dosage of famitinib or a pharmaceutically acceptable salt thereof is provided, comprising administering the above anti-CTAL-4 antibody in combination with famitinib to a patient. Ni or its pharmaceutically acceptable salt.
在可選實施方案中,與PD-L1聯合使用時,該法米替尼或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%(包括10%、15%、20%、30%、35%、40%、45%、50%、55%、60%、70%、75%、80%、90%、95%),較佳10%~75%,更佳75%、50%、25%、12.5%。 In an optional embodiment, when used in combination with PD-L1, the dosage of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% (including 10%, 15%, 20%) of the dosage administered alone. %, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10%~75%, preferably 75 %, 50%, 25%, 12.5%.
在可選實施方案中,與法米替尼或其可藥用鹽聯用時,抗PD-L1抗體劑量是抗PD-L1抗體單獨施用劑量的10%~100%(包括10%、15%、20%、30%、35%、40%、45%、50%、55%、60%、70%、75%、80%、90%、95%),較佳10%~50%。 In alternative embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the anti-PD-L1 antibody dose is 10% to 100% (including 10%, 15%) of the anti-PD-L1 antibody dose administered alone. , 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10%~50%.
在可選實施方案中,與抗CTAL-4抗體聯合使用時,該法米替尼或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%,較佳10%~75%,更佳75%、50%、25%、12.5%。 In an optional embodiment, when used in combination with an anti-CTAL-4 antibody, the dosage of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100% of the dosage administered alone, preferably 10% to 75% %, better 75%, 50%, 25%, 12.5%.
在可選實施方案中,與法米替尼或其可藥用鹽聯用時,抗CTAL-4抗體劑量是抗CTAL-4抗體單獨施用劑量的10%~100%,較佳10%~50%。 In alternative embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the anti-CTAL-4 antibody dose is 10% to 100% of the anti-CTAL-4 antibody dose administered alone, preferably 10% to 50% %.
本公開中還提供了一種藥物套組,或者一種藥物包裝盒,其中含有法米替尼或其可藥用鹽,和PD-L1抗體或CTAL-4抗體。 The present disclosure also provides a drug set, or a drug packaging box, which contains famitinib or a pharmaceutically acceptable salt thereof, and a PD-L1 antibody or a CTAL-4 antibody.
在本公開中的用途中,該腫瘤示例選自但不限於:乳腺癌(如三陰性乳腺癌)、肺癌、胃癌、腸癌(如直腸癌、結直腸癌)、腎癌(如腎細胞癌)、肝癌(如原發性肝癌、肝細胞癌、膽管細胞癌、轉移性肝癌、繼發性肝癌)、黑素瘤(如轉移性黑色瘤)、非小細胞肺癌、尿路上皮癌(如膀胱癌、輸尿管、尿道癌)、宮頸癌、卵巢癌(如復發性卵巢癌)、子宮內膜癌、成淋巴細胞T細胞白血病、慢性髓細胞性白血病、甲狀腺癌、慢性淋巴細胞白血病、毛細胞白血病、急性成淋巴細胞性白血病、急性髓細胞白血病(AML)、慢性中性粒細胞白血病、急性成淋巴細胞T細胞白血病、免疫母細胞大細胞白血病、套細胞白血病、多發性骨髓瘤巨核母細胞白血病、急性巨核細胞白血病、早幼粒細胞白血病、紅白血病、惡性淋巴瘤、多發性骨髓瘤、漿細胞瘤、霍奇金淋巴瘤、非霍奇金淋巴 瘤、淋巴母細胞T細胞淋巴瘤、伯基特淋巴瘤、濾泡性淋巴瘤、骨髓增生異常綜合征(MDS)。 For use in the present disclosure, the tumor examples are selected from, but are not limited to: breast cancer (such as triple negative breast cancer), lung cancer, gastric cancer, intestinal cancer (such as rectal cancer, colorectal cancer), kidney cancer (such as renal cell carcinoma) ), liver cancer (such as primary liver cancer, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver cancer, secondary liver cancer), melanoma (such as metastatic melanoma), non-small cell lung cancer, urothelial cancer (such as Bladder cancer, ureter, urethra cancer), cervical cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, thyroid cancer, chronic lymphocytic leukemia, hairy cell Leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblast Leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin lymphoma, non-Hodgkin lymphoma tumour, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, myelodysplastic syndrome (MDS).
在可選實施方案中,本公開用途中腫瘤為非小細胞肺癌、甲狀腺癌、乳腺癌(如三陰性乳腺癌)、黑素瘤(如轉移性黑色瘤)、腎癌、尿路上皮癌(如膀胱癌、輸尿管、尿道癌)、宮頸癌、甲狀腺癌、卵巢癌(如復發性卵巢癌)、子宮內膜癌、腸癌或肝癌。 In alternative embodiments, the tumor for use in the present disclosure is non-small cell lung cancer, thyroid cancer, breast cancer (such as triple negative breast cancer), melanoma (such as metastatic melanoma), renal cancer, urothelial cancer ( Such as bladder cancer, ureter, urethra cancer), cervical cancer, thyroid cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, bowel cancer or liver cancer.
在較佳實施方案中,該腫瘤患者為接受過鉑類藥物治療的。例如接受鉑類藥物治療失敗或者不可耐受的患者,或者接受鉑治療方案治療期間或治療結束後<6個月進展或復發。 In a preferred embodiment, the tumor patient has been treated with platinum-based drugs. For example, patients who have failed or cannot tolerate platinum therapy, or who have progressed or relapsed during or <6 months after receiving platinum therapy.
在一些實施方案中,本公開用途中該腫瘤為腎癌(腎細胞癌)。較佳地,為組織或細胞學確診的晚期腎透明細胞癌(混合型腫瘤,如腎透明細胞癌)。 In some embodiments, the tumor for use in the present disclosure is kidney cancer (renal cell carcinoma). Preferably, it is advanced clear cell renal cell carcinoma (mixed tumor, such as clear cell renal cell carcinoma) confirmed by tissue or cytology.
在較佳實施方案中,本公開用途中該腎細胞癌患者為既往經過白細胞介素-2和/或抗血管新生靶向藥治療、治療失敗的。 In a preferred embodiment, the patient with renal cell carcinoma used in the present disclosure has previously been treated with interleukin-2 and/or anti-angiogenesis targeted drugs and the treatment failed.
在一些實施方案中,本公開用途中該腫瘤為尿路上皮癌(如膀胱癌、輸尿管、尿道癌)。較佳地,為組織或細胞學確診的無法根治的尿路上皮癌(如包括腎盂癌、輸尿管癌、膀胱癌及尿道癌,混合型癌如組織學類型為移行細胞癌亞型)。 In some embodiments, the tumor for use in the present disclosure is urothelial cancer (eg, bladder cancer, ureter, urethra cancer). Preferably, it is incurable urothelial cancer confirmed by tissue or cytology (for example, including renal pelvis cancer, ureteral cancer, bladder cancer and urethral cancer, mixed cancer such as the histological type is transitional cell carcinoma subtype).
在較佳實施方案中,本公開用途中該尿路上皮癌患者為接受過鉑類藥物治療的。例如,接受接受鉑類藥物治療失敗或者不可耐受的患者,或者接受鉑治療方案治療期間或治療結束後進展或復發。 In a preferred embodiment, the urothelial cancer patient in the disclosed uses has been treated with platinum-based drugs. For example, patients who have failed or are intolerant to platinum-based therapy, or who have progressed or relapsed during or after treatment with a platinum-based regimen.
在一些實施方案中,本公開用途中該腫瘤為宮頸癌。較佳地,為組織或細胞學確認的晚期宮頸鱗狀細胞癌。 In some embodiments, the tumor in the disclosed uses is cervical cancer. Preferably, it is advanced cervical squamous cell carcinoma confirmed by tissue or cytology.
在較佳實施方案中,該宮頸癌患者為既往經過1線系統治療失敗的。 In a preferred embodiment, the cervical cancer patient has a history of The first line of systemic treatment failed.
在另一些實施方案中,本公開用途中該腫瘤為卵巢癌,較佳地,為復發性卵巢癌,進一步地,為組織病理學確診的復發性卵巢上皮癌、輸卵管癌或原發性腹膜癌。 In other embodiments, the tumor is ovarian cancer, preferably, recurrent ovarian cancer, and further, histopathologically confirmed recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. .
在較佳實施方案中,該復發性卵巢癌患者為接受過鉑類藥物治療的。例如接受鉑類藥物治療失敗或者不可耐受的患者,或者接受鉑治療方案治療期間或治療結束(完成4程及以上治療)後<6個月進展或復發。 In a preferred embodiment, the patient with recurrent ovarian cancer has received platinum-based drug treatment. For example, patients who have failed or are intolerable to platinum-based drug therapy, or who have progressed or relapsed during treatment or <6 months after completing 4 courses of treatment or more after receiving a platinum-based treatment regimen.
在另一些實施方案中個,本公開用途中該腫瘤為子宮內膜癌,較佳地,為組織病理學確診的子宮內膜癌。在較佳實施方案中,該子宮內膜癌患者為接受過鉑類藥物治療的。例如,例如接受鉑類藥物治療失敗或者不可耐受的患者,或者接受鉑治療方案治療期間或治療結束(完成4程及以上治療)後<6個月進展或復發。 In other embodiments, the tumor in the presently disclosed uses is endometrial cancer, preferably, is histopathologically confirmed endometrial cancer. In a preferred embodiment, the endometrial cancer patient has received platinum-based drug treatment. For example, patients who have failed or are intolerant to platinum-based drug therapy, or who have progressed or relapsed <6 months after receiving a platinum-based regimen or after completing 4 courses of treatment or more.
本公開中還提供了一種法米替尼或其可藥用鹽在製備治療受益於抑制TYRO3和/或AXL和/或MER的病症的藥物中的用途。 Also provided in the present disclosure is the use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition that benefits from inhibition of TYRO3 and/or AXL and/or MER.
本公開中還提供了一種法米替尼或其可藥用鹽治療受益於抑制TYRO3和/或AXL和/或MER的病症的方法,包括向患者施用上述法米替尼或其可藥用鹽。進一步地,在可選實施方案中,該法米替尼或其可藥用鹽是可單用或聯用。 The present disclosure also provides a method for treating a condition benefiting from inhibition of TYRO3 and/or AXL and/or MER with famitinib or a pharmaceutically acceptable salt thereof, comprising administering the above famitinib or a pharmaceutically acceptable salt thereof to a patient . Further, in optional embodiments, famitinib or a pharmaceutically acceptable salt thereof can be used alone or in combination.
進一步地,在可選實施方案中,該法米替尼或其可藥用鹽是可以單獨施用或聯合施用的。 Further, in optional embodiments, the famitinib or a pharmaceutically acceptable salt thereof can be administered alone or in combination.
本公開中該受益於抑制TYRO3(Tyro3 tyrosine kinase receptor inhibitor)和/或AXL(Axl tyrosine kinase receptor inhibitor)和/或MER(Mer tyrosine kinase receptor inhibitor)的病症示例包括但不限於:成淋巴細胞T細胞白血病、慢性髓細胞性白血病、慢性淋巴細胞白血病、毛細胞白血病、急性成淋巴細胞性白血病、急性髓細胞白血病(AML)、慢性中性粒細胞白血病、急性成淋巴細胞T細胞白血病、免疫母細胞大細胞白血病、套細胞白血病、多發性骨髓瘤巨核母細胞白血病、急性巨核細胞白血病、早幼粒細胞白血病、紅白血病、惡性淋巴瘤、多發性骨髓瘤、漿細胞瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴母細胞T細胞淋巴瘤、伯基特淋巴瘤、濾泡性淋巴瘤,骨髓增生異常綜合征(MDS)、血栓性病症(如心肌梗死、缺血性腦梗塞、外周血管病、靜脈血栓栓塞等),等等。 In this disclosure, examples of conditions that benefit from inhibition of TYRO3 (Tyro3 tyrosine kinase receptor inhibitor) and/or AXL (Axl tyrosine kinase receptor inhibitor) and/or MER (Mer tyrosine kinase receptor inhibitor) include but are not limited to: lymphoblastic T cells Leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, immunoblast Large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, myelodysplastic syndrome (MDS), thrombotic disorders (such as myocardial infarction, ischemic cerebral infarction, Peripheral vascular disease, venous thromboembolism, etc.), etc.
本公開中該法米替尼可藥用的鹽選自但不限於甲磺酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、醋酸鹽、二氟醋酸鹽、富馬酸鹽、檸檬酸鹽、枸櫞酸鹽、苯磺酸鹽、苯甲酸鹽、萘磺酸鹽、乳酸鹽、蘋果酸鹽、鹽酸鹽、氫溴酸鹽、硫酸鹽、以及磷酸鹽,較佳蘋果酸鹽。 In the present disclosure, the pharmaceutically acceptable salt of famitinib is selected from but not limited to mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citric acid Salt, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, preferably malate .
在一些所述方案中,本公開中法米替尼可藥用的鹽在人類受試者中的施用劑量以自由堿形式計算。 In some such embodiments, the dosage of a pharmaceutically acceptable salt of famitinib administered in a human subject of the present disclosure is calculated as the free salt.
如無相反解釋,本公開中術語具有如下含義: Unless otherwise interpreted, terms used in this disclosure have the following meanings:
本公開關於“AUC”是指藥物代謝動力學血藥濃度曲線對時間軸所包圍的面積,該參數是評價藥物吸收程度的重要指標,反映藥物在體內的暴露特性。由於藥動學研究中血藥濃度只能觀察至某時間點t,因此AUC有兩種表 示方式:AUC(0-t)和AUC(0-∞),前者根據梯形面積法得到,後者計算式:AUC(0-∞)=AUC(0-t)+末端點濃度/末端消除速率。本申請中該AUC是指單次給藥或多次給藥達到穩態後患者的平均AUC0-24,較佳多次給藥達到穩態後患者的平均AUC0-24(即AUCss)。 In this disclosure, “AUC” refers to the area enclosed by the pharmacokinetic blood drug concentration curve against the time axis. This parameter is an important indicator for evaluating the degree of drug absorption and reflects the exposure characteristics of the drug in the body. Since the blood drug concentration in pharmacokinetic studies can only be observed up to a certain time point t, there are two forms of AUC. Expression method: AUC(0-t) and AUC(0-∞), the former is obtained according to the trapezoid area method, and the latter is calculated by: AUC(0-∞)=AUC(0-t)+end point concentration/end elimination rate. In this application, the AUC refers to the average AUC0-24 of patients after a single dose or multiple doses to reach steady state, preferably the average AUC0-24 of patients after multiple doses to reach steady state (i.e. AUCss).
本公開關於“聯合”是一種給藥方式,是指在一定時間期限內給予至少一種劑量的法米替尼或可藥用鹽,和少一種劑量的抗PD-1抗體或其抗原結合片段,其中兩種物質都顯示藥理學作用。該時間期限可以是一個給藥週期內,較佳4週內,3週內,2週內,1週內,或24小時以內。可以同時或依次給予法米替尼或可藥用鹽和抗PD-1抗體或其抗原結合片段。這種期限包括這樣的治療,其中藉由相同給藥途徑或不同給藥途徑給予法米替尼或可藥用鹽和抗PD-1抗體或其抗原結合片段。本公開所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。總生存期(OS)指從隨機期至任何原因導致死亡的期。末次隨訪時仍存活的受試者,其OS以末次隨訪時間計為數據刪失。失訪的受試者,其OS以失訪前末次證實存活時間計為數據刪失。數據刪失的OS定義為從隨機分組到刪失的時間。 In this disclosure, "combination" refers to a method of administration, which refers to the administration of at least one dose of famitinib or a pharmaceutically acceptable salt and one less dose of anti-PD-1 antibody or antigen-binding fragment thereof within a certain period of time, Two of these substances show pharmacological effects. The time period may be within one dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. Famitinib or a pharmaceutically acceptable salt and an anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously or sequentially. Such periods include treatments in which famitinib or a pharmaceutically acceptable salt and an anti-PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or by different routes of administration. The administration mode of the combination described in the present disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and administered sequentially. Overall survival (OS) refers to the period from randomization to death from any cause. For subjects who were still alive at the last follow-up, their OS was calculated based on the time of the last follow-up and the data was censored. For subjects who were lost to follow-up, their OS was calculated as the last confirmed survival time before being lost to follow-up as data censoring. The OS of data censoring is defined as the time from randomization to censoring.
客觀緩解率(Objective response rate,ORR)指腫瘤縮小達到一定並且保持一定時間的病人的比例,包含了CR和PR的病例。採用實體瘤緩解評估標準(RECIST 1.1標準)來評定腫瘤客觀緩解。受試者在基線時必須伴有可測量的腫瘤病灶,療效評定標準根據RECIST 1.1標準分為完全緩解(CR)、部分緩解(PR)、穩定(SD)、進展(PD)。 Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain level and remain for a certain period of time, including cases of CR and PR. Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria) was used to evaluate objective tumor response. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable (SD), and progression (PD) according to RECIST 1.1 standards.
疾病控制率(Disease Control Rate,DCR)指經確認的完全緩解、部分緩解和疾病穩定(8週)病例數在可評價療效患者中的百分比。 Disease Control Rate (DCR) refers to confirmed complete remission, partial remission and stable disease ( 8 weeks) number of cases as a percentage of patients evaluable for efficacy.
完全緩解(CR):所有靶病灶消失,全部病理淋巴結(包括靶結節和非靶結節)短直徑必須減少至<10mm。 Complete response (CR): All target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.
部分緩解(PR):靶病灶直徑之和比基線水平減少至少30%。 Partial response (PR): The sum of target lesion diameters is reduced by at least 30% from baseline.
疾病進展(PD):以整個實驗研究過程中所有測量的靶病灶直徑之和的最小值為參照,直徑和相對增加至少20%(如果基線測量值最小就以基線值為參照);除此之外,必須滿足直徑和的絕對值增加至少5mm(出現一個或多個新病灶也視為疾病進展)。 Disease progression (PD): Taking the minimum value of the sum of the diameters of all target lesions measured during the entire experimental study as a reference, the diameter sum has a relative increase of at least 20% (if the baseline measurement value is the smallest, the baseline value is used as the reference); otherwise In addition, the absolute value of the diameter and sum must be increased by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).
疾病穩定(SD):靶病灶減小的程度沒達到PR,增加的程度也沒達到PD水平,介於兩者之間,研究時可以直徑之和的最小值作為參考。 Stable disease (SD): The reduction of the target lesion does not reach the PR level, and the increase does not reach the PD level. It is somewhere in between. The minimum value of the sum of diameters can be used as a reference during research.
“mpk”:毫克/每公斤。 "mpk": mg/kg.
本公開中所用試劑、生物樣品或活性物可藉由商業途徑獲得,如所用人PD-1轉基因小鼠,4-5週齡,可從英國Cephrim Biosciences,Inc公司購買。 The reagents, biological samples or active substances used in the present disclosure can be obtained through commercial channels. For example, the human PD-1 transgenic mice used, 4-5 weeks old, can be purchased from Cephrim Biosciences, Inc. in the UK.
以下結合實施例用於進一步描述本公開,但這些實施例並非限制本公開的範圍。 The following examples are used to further describe the disclosure, but these examples do not limit the scope of the disclosure.
實施例1: Example 1:
以人PD-1轉基因小鼠為受試動物,評價PD-1抗體和法米替尼聯用後對轉入PD-L1基因的小鼠結腸癌細胞MC-38(PD-L1)移植瘤C57人PD-1轉基因小鼠的療效。 Human PD-1 transgenic mice were used as test animals to evaluate the effect of the combination of PD-1 antibody and famitinib on mouse colon cancer cell MC-38 (PD-L1) transplanted tumor C57 that was transferred with the PD-L1 gene. Efficacy of human PD-1 transgenic mice.
化合物A:PD-1抗體,其重、輕鏈的序列如本公開中SEQID NO:7和SEQID NO:8。200mg/每瓶,配成20mg/ml備用。 Compound A: PD-1 antibody, the sequences of its heavy and light chains are as SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure. 200 mg/bottle, prepared as 20 mg/ml for later use.
化合物B:蘋果酸法米替尼,可按照專利申請WO2007085188中的方法製備。 Compound B: famitinib malate, can be prepared according to the method in patent application WO2007085188.
試驗方案: Test plan:
在7天時將MC38細胞(5 x105)接種於40隻人PD-1轉基因小鼠(包括雌雄2種性別)右肋部皮下,待小鼠平均腫瘤體積達到100mm3左右時,選取32隻,隨機分成4組,每組8隻。分組後根據方案分別給予溶媒對照、腹腔注射化合物A、口服灌胃化合物及兩者聯合用藥。每週兩次測瘤體積,稱體重,記錄數據。 At 7 days, MC38 cells (5 x105) were inoculated subcutaneously into the right ribs of 40 human PD-1 transgenic mice (including both sexes). When the average tumor volume of the mice reached about 100mm3 , 32 mice were selected. Randomly divide into 4 groups, 8 animals in each group. After grouping, the subjects were given vehicle control, intraperitoneal injection of compound A, oral gavage compound, or a combination of the two according to the protocol. Tumor volume was measured twice a week, body weight was weighed, and data were recorded.
本次實驗結果顯示,PD-1抗體(3mpk)與蘋果酸法米替尼(10mpk)聯用組的藥效是優於PD-1抗體、蘋果酸法米替尼單用的藥效。給藥各組小鼠體重正常,顯示藥物無明顯毒副作用。 The results of this experiment show that the efficacy of the combination of PD-1 antibody (3mpk) and famitinib malate (10mpk) is better than the efficacy of PD-1 antibody and famitinib malate alone. The mice in each drug group had normal body weight, showing that the drug had no obvious toxic or side effects.
實施例2:蘋果酸法米替尼對體外TYRO3、AXL、MER激酶活性的影響 Example 2: Effect of famitinib malate on TYRO3, AXL, and MER kinase activities in vitro
(1)IC50ProfilerTM實驗步驟 (1)IC50Profiler TM experimental steps
將適量激酶、多肽受質,分別和不同濃度的蘋果酸法米替尼(1nM、3nM、10nM、30nM、100nM、300nM、1μM、3μM、10μM)混勻,在室溫下孵育60min。加入醋酸鎂和[gamma-33P]-ATP啟動激酶催化反應,室溫下反應40分鐘。反應結束後加入3%的磷酸溶液終止反應。取反應混合物10μL,加入到P30濾膜中過濾,75mM的磷酸緩衝液清膜3次,用甲醇洗一次,去除游離的[gamma-33P]-ATP並固定蛋白,將膜烘乾,液閃儀計數,測定多肽受質是的33P的量。 Mix an appropriate amount of kinase and peptide substrate with different concentrations of famitinib malate (1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1μM, 3μM, 10μM) respectively, and incubate at room temperature for 60 minutes. Magnesium acetate and [gamma-33P]-ATP were added to start the kinase catalytic reaction, and the reaction was carried out at room temperature for 40 minutes. After the reaction, 3% phosphoric acid solution was added to terminate the reaction. Take 10 μL of the reaction mixture, add it to a P30 filter membrane and filter, clear the membrane three times with 75mM phosphate buffer, and wash it once with methanol to remove free [gamma-33P]-ATP and fix the protein. Dry the membrane and use a liquid scintillation analyzer. Count and determine the amount of 33P in the polypeptide substrate.
(2)試驗結果 (2)Test results
根據濃度-抑制曲線,擬合後得到的IC50值見表1 According to the concentration-inhibition curve, the IC50 value obtained after fitting is shown in Table 1
實施例3: Example 3:
1、受試抗體和化合物 1. Test antibodies and compounds
化合物A:其重、輕鏈的序列如本公開中SEQID NO:7和SEQID NO:8。200mg/每瓶,配成20mg/ml備用; Compound A: The sequences of its heavy and light chains are as follows: SEQ ID NO: 7 and SEQ ID NO: 8 in this disclosure. 200 mg/bottle, mixed into 20 mg/ml for later use;
化合物B:蘋果酸法米替尼,可按照專利申請WO2007085188中的方法製備。 Compound B: famitinib malate, can be prepared according to the method in patent application WO2007085188.
2、入組標準:晚期腎癌、尿路上皮癌、宮頸癌、復發性卵巢癌及子宮內膜癌患者 2. Inclusion criteria: patients with advanced renal cancer, urothelial cancer, cervical cancer, recurrent ovarian cancer and endometrial cancer
(1)針對腎細胞癌:組織或細胞學確診的晚期腎透明細胞癌(混合型腫瘤,如腎透明細胞癌佔主要成分可以入組);原發灶經過手術切除,且既往經過白細胞介素-2和/或抗血管新生靶向藥治療、治療失敗; (1) For renal cell carcinoma: advanced renal clear cell carcinoma confirmed by tissue or cytology (mixed tumor, such as renal clear cell carcinoma as the main component can be included); the primary tumor has been surgically removed and has been treated with interleukin in the past -2 and/or anti-angiogenesis targeted drug treatment or treatment failure;
(2)針對尿路上皮癌:組織或細胞學確診的無法根治的尿路上皮癌,包括腎盂癌、輸尿管癌、膀胱癌及尿道癌,混合型癌要求主要的組織學類型為移行細胞癌亞型;既往經過含鉑類方案治療進展或復發,且既往系統治療方案數不超過2個。 (2) For urothelial cancer: Incurable urothelial cancer confirmed by tissue or cytology, including renal pelvis cancer, ureteral cancer, bladder cancer and urethral cancer. The main histological type of mixed cancer is transitional cell carcinoma subtype. Type; has previously progressed or relapsed after treatment with platinum-containing regimens, and the number of previous systemic treatment regimens does not exceed 2.
(3)針對宮頸癌:組織或細胞學確認的晚期宮頸鱗狀細胞癌;既往經過1線系統治療失敗; (3) For cervical cancer: advanced cervical squamous cell carcinoma confirmed by tissue or cytology; past experience Failure of first-line systemic treatment;
(4)針對復發性卵巢癌:組織病理學確診的復發性卵巢上皮癌、輸卵管癌或原發性腹膜癌,既往經過以鉑類為基礎的方案治療,且最後一次含鉑治療方案治療期間或治療結束(完成4程及以上治療)後<6個月進展或復發; (4) For recurrent ovarian cancer: Recurrent ovarian epithelial cancer, fallopian tube cancer or primary peritoneal cancer confirmed by histopathology, previously treated with a platinum-based regimen, and during the last platinum-containing regimen or Progress or relapse <6 months after completion of treatment (completion of 4 courses or more of treatment);
(5)針對子宮內膜癌:組織病理學確診的子宮內膜癌,既往至少經過以鉑類為基礎的方案治療,治療結束後或治療期間,疾病復發或進展。 (5) Endometrial cancer: Endometrial cancer confirmed by histopathology has been treated with at least a platinum-based regimen in the past, and the disease recurs or progresses after the end of treatment or during treatment.
3、給藥方案: 3. Dosage plan:
化合物A:靜脈注射,200mg,3週給藥1次,每3週1週期;化合物B:20mg或15mg,口服,一日一次。 Compound A: intravenous injection, 200 mg, once every 3 weeks, 1 cycle every 3 weeks; Compound B: 20 mg or 15 mg, oral administration, once a day.
4、安全性數據 4. Safety data
化合物A與化合物B聯用時,未觀察到研究藥物相關死亡。雖然3級及以上不良事件發生率為60%,但都可控。毒性反應多為與化合物B用藥相關的毒性,可藉由糾正治療,暫停化合物B給藥得到有效控制。研究者判斷的免疫相關不良事件發生率低(13.8%)且基本上都是較低級別的不良事件,僅1例為3級急性腸炎,其他均為2級及以下不良事件。另外,兩藥聯用,僅2例(2.5%)受試者發生反應性皮膚毛細血管增生症,顯著低於化合物A單藥治療實體瘤的發生率(54.3%),提示聯合化合物B或可降低化合物A的不良反應。總體嚴重不良事件發生率不高,僅2例(2.5%)受試者因SAE退出治療。為此,化合物A與化合物B聯合給藥用於泌尿系統腫瘤和婦科腫瘤的安全性良好。 No study drug-related deaths were observed when Compound A was administered in combination with Compound B. Although the incidence rate of grade 3 and above adverse events is 60%, they are all controllable. Toxic reactions are mostly related to the administration of Compound B and can be effectively controlled by corrective treatment and suspending the administration of Compound B. The incidence of immune-related adverse events judged by the researchers was low (13.8%) and they were basically lower-grade adverse events. Only one case was grade 3 acute enteritis, and the others were grade 2 and below adverse events. In addition, when the two drugs were used in combination, only 2 subjects (2.5%) developed reactive skin capillary hyperplasia, which was significantly lower than the incidence rate of compound A (54.3%) in the treatment of solid tumors with single drug, suggesting that the combination of compound B may be effective. Reduce the adverse reactions of compound A. The overall incidence of serious adverse events was low, with only 2 subjects (2.5%) withdrawing from treatment due to SAE. For this reason, the safety of combined administration of Compound A and Compound B for urinary system tumors and gynecological tumors is good.
5、有效性 5. Effectiveness
80例受試者中75例進行了至少一次療效評價,5例因首次療評前已出組或 死亡導致無法評估。 Among the 80 subjects, 75 subjects underwent at least one efficacy evaluation, and 5 subjects were discharged from the group or received treatment before the first treatment assessment. Death renders assessment impossible.
腎癌隊列25例受試者中23例進行了療效評價,12例受試者表現為部分緩解(PR),9例受試者表現為疾病穩定(SD),2例為疾病進展(PD),客觀緩解率(ORR)為52.2%,疾病控制率(DCR)為91.3%,優於化合物B25mg、qd、單藥治療腎癌的ORR(36%)。 Among the 25 subjects in the kidney cancer cohort, 23 subjects were evaluated for efficacy, 12 subjects showed partial response (PR), 9 subjects showed stable disease (SD), and 2 subjects showed progressive disease (PD). , the objective response rate (ORR) was 52.2%, and the disease control rate (DCR) was 91.3%, which is better than the ORR (36%) of Compound B 25mg, qd, single drug treatment of renal cancer.
尿路上皮癌隊列10例受試者中9例進行了療效評價,3例受試者表現為部分緩解(PR),3例受試者表現為疾病穩定(SD),3例為疾病進展(PD),客觀緩解率(ORR)為33.3%,疾病控制率(DCR)為66.7%。 In the urothelial cancer cohort, 9 out of 10 subjects were evaluated for efficacy, 3 subjects showed partial response (PR), 3 subjects showed stable disease (SD), and 3 subjects showed progressive disease ( PD), the objective response rate (ORR) was 33.3%, and the disease control rate (DCR) was 66.7%.
卵巢癌隊列24例受試者均進行了療效評價,8例受試者表現為部分緩解(PR),10例受試者表現為疾病穩定(SD),7例為疾病進展(PD),客觀緩解率(ORR)為33.3%,疾病控制率(DCR)為75%。 All 24 subjects in the ovarian cancer cohort were evaluated for efficacy. 8 subjects showed partial response (PR), 10 subjects showed stable disease (SD), and 7 subjects showed progressive disease (PD). Objectively The response rate (ORR) was 33.3% and the disease control rate (DCR) was 75%.
子宮內膜癌隊列5例受試者中4例進行了療效評價,2例受試者表現為部分緩解(PR),1例受試者表現為疾病穩定(SD),1例為疾病進展(PD),客觀緩解率(ORR)為50%,疾病控制率(DCR)為75%。 In the endometrial cancer cohort, 4 out of 5 subjects were evaluated for efficacy, 2 subjects showed partial response (PR), 1 subject showed stable disease (SD), and 1 subject showed progressive disease ( PD), the objective response rate (ORR) was 50%, and the disease control rate (DCR) was 75%.
宮頸癌隊列16例受試者中15例進行了療效評價,8例受試者表現為部分緩解(PR),5例受試者表現為疾病穩定(SD),2例為疾病進展(PD),客觀緩解率(ORR)為53.3%,疾病控制率(DCR)為86.7%。 Among the 16 subjects in the cervical cancer cohort, 15 subjects were evaluated for efficacy, 8 subjects showed partial response (PR), 5 subjects showed stable disease (SD), and 2 subjects showed progressive disease (PD). , the objective response rate (ORR) was 53.3%, and the disease control rate (DCR) was 86.7%.
總體上,80例受試者中75例進行了至少一次療效評價,33例受試者表現為部分緩解(PR),27例受試者表現為疾病穩定(SD),15例為疾病進展(PD),客觀緩解率(ORR)為44.0%,疾病控制率(DCR)為80.0%。 Overall, 75 of 80 subjects underwent at least one efficacy evaluation, 33 subjects showed partial response (PR), 27 subjects showed stable disease (SD), and 15 subjects showed progressive disease ( PD), the objective response rate (ORR) was 44.0%, and the disease control rate (DCR) was 80.0%.
6、藥物代謝動力學 6. Pharmacokinetics
在12例參加藥物代謝動力學研究的受試者中,採集了9例受試者PK血。 Among the 12 subjects participating in the pharmacokinetic study, PK blood was collected from 9 subjects.
結果顯示,化合物A與化合物B聯用下的化合物B的暴露量較化合物B單用有所增加,化合物B的PK參數(包括Css,min,Css,max,AUCss)優於單藥。 The results showed that the exposure of Compound B when Compound A was combined with Compound B was increased compared to Compound B alone, and the PK parameters of Compound B (including Css, min, Css, max, AUCss) were better than those of the single drug.
7、小結 7. Summary
化合物A與化合物B聯合給藥,耐受性良好、毒性可控、可耐受,同時聯合給藥能夠有效降低化合物A常見的不良反應-反應性毛細血管增生症的發生,療效較好。 The combined administration of Compound A and Compound B has good tolerance, controllable toxicity, and tolerability. Simultaneous administration can effectively reduce the occurrence of reactive capillary hyperplasia, a common adverse reaction of Compound A, and has good efficacy.
<110> 江蘇恆瑞醫藥股份有限公司(JIANGSU HENGRUI PHARMACEUTICALS CO.,LTD.) 蘇州盛迪亞生物醫藥有限公司(SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.) <110>JIANGSU HENGRUI PHARMACEUTICALS CO.,LTD. Suzhou SUNCADIA BIOPHARMACEUTICALS CO.,LTD.
<120> 一種抗PD-1抗體和法米替尼聯合在製備治療腫瘤的藥物中的用途 <120> Use of a combination of anti-PD-1 antibody and famitinib in the preparation of drugs for treating tumors
<150> CN201811313004.X <150> CN201811313004.X
<151> 2018-11-06 <151> 2018-11-06
<160> 10 <160> 10
<170> SIPOSequenceListing 1.0 <170> SIPOSequenceListing 1.0
<210> 1 <210> 1
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<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 1 <400> 1
<210> 2 <210> 2
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<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 2 <400> 2
<210> 3 <210> 3
<211> 7 <211> 7
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 3 <400> 3
<210> 4 <210> 4
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<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
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<211> 7 <211> 7
<212> PRT <212> PRT
<213> 鼠源(Mus musculus) <213> Mus musculus
<400> 5 <400> 5
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<212> PRT <212> PRT
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<221> 肽 <221> Peptide
<222> (1)..(443) <222> (1)..(443)
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<212> PRT <212> PRT
<213> 人工序列(Artificial Sequence) <213> Artificial Sequence
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